A Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND): Protocol for a Prospective Study
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JMIR RESEARCH PROTOCOLS Diepstraten et al
Protocol
A Study on Prevalence and Determinants of Ototoxicity During
Treatment of Childhood Cancer (SOUND): Protocol for a
Prospective Study
Franciscus A Diepstraten1, MSc, MD; Annelot JM Meijer1, PhD; Martine van Grotel1, MD, PhD; Sabine LA
Plasschaert1, MD, PhD; Alexander E Hoetink2,3, PhD; Marta Fiocco1,4,5, PhD; Geert O Janssens6, MD, PhD; Robert
J Stokroos2,3, MD, PhD; Marry M van den Heuvel-Eibrink1, MD, PhD
1
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
2
Department of Otorhinolaryngology and Head & Neck Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
3
University Medical Center Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands
4
Mathematical Institute, Leiden University, Leiden, the Netherlands
5
Department of Biomedical Data Science, Section Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands
6
Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, the Netherlands
Corresponding Author:
Franciscus A Diepstraten, MSc, MD
Princess Máxima Center for Pediatric Oncology
Heidelberglaan 25
Utrecht, 3584 CS
The Netherlands
Phone: 31 625710488
Email: f.a.diepstraten@prinsesmaximacentrum.nl
Abstract
Background: Some children with central nervous system (CNS) and solid tumors are at risk to develop ototoxicity during
treatment. Up to now, several risk factors have been identified that may contribute to ototoxicity, such as platinum derivates,
cranial irradiation, and brain surgery. Comedication, like antibiotics and diuretics, is known to enhance ototoxicity, but their
independent influence has not been investigated in childhood cancer patients. Recommendations for hearing loss screening are
missing or vary highly across treatment protocols. Additionally, adherence to existing screening guidelines is not always optimal.
Currently, knowledge is lacking on the prevalence of ototoxicity.
Objective: The aim of the Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer
(SOUND) is to determine the feasibility of audiological testing and to determine the prevalence and determinants of ototoxicity
during treatment for childhood cancer in a national cohort of patients with solid and CNS tumors.
Methods: The SOUND study is a prospective cohort study in the national childhood cancer center in the Netherlands. The study
aims to include all children aged 0 to 19 years with a newly diagnosed CNS or solid tumor. Part of these patients will get
audiological examination as part of their standard of care (stratum 1). Patients in which audiological examination is not the
standard of care will be invited for inclusion in stratum 2. Age-dependent audiological assessments will be pursued before the
start of treatment and within 3 months after the end of treatment. Apart from hearing loss, we will investigate the feasibility to
screen patients for tinnitus and vertigo prevalence after cancer treatment. This study will also determine the independent contribution
of antibiotics and diuretics on ototoxicity.
Results: This study was approved by the Medical Research Ethics Committee Utrecht (Identifier 20-417/M). Currently, we are
in the process of recruitment for this study.
Conclusions: The SOUND study will raise awareness about the presence of ototoxicity during the treatment of children with
CNS or solid tumors. It will give insight into the prevalence and independent clinical and cotreatment-related determinants of
ototoxicity. This is important for the identification of future high-risk patients. Thereby, the study will provide a basis for the
selection of patients who will benefit from innovative otoprotective intervention trials during childhood cancer treatment that are
currently being prepared.
Trial Registration: Netherlands Trial Register NL8881; https://www.trialregister.nl/trial/8881
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International Registered Report Identifier (IRRID): DERR1-10.2196/34297
(JMIR Res Protoc 2022;11(4):e34297) doi: 10.2196/34297
KEYWORDS
pediatrics; ototoxicity; audiometry; antibiotics; diuretics; radiotherapy; solid tumors; neuro-oncology; audiology; cancer; children
as it will aid in the timely detection of symptomatic or
Introduction asymptomatic hearing loss and early referral to an audiologist.
Each year around 600 children are newly diagnosed with cancer In certain circumstances, alternative cancer treatment options
in the Netherlands [1]. Over the past decades, cancer diagnostics may be considered depending on the child’s diagnosis and
and treatment have improved, resulting in an overall survival evidence-based alternative treatments.
up to about 80% in high-income countries [2]. Due to the In the Princess Máxima Center for Pediatric Oncology, the
increased survival, more awareness has been raised for sequelae Study on Prevalence and Determinants of Ototoxicity During
of childhood cancer treatment. A serious direct and late effect Treatment of Childhood Cancer (SOUND) was started in
of treatment includes ototoxicity, which involves the destruction January 2021. We intend to invite 600 patients in this study
of cochlear structures leading to hearing loss, tinnitus (ear over a period of 24 months. This number is based on the number
ringing), or vertigo (dizziness) [3,4]. Ototoxicity in childhood of children diagnosed with solid and CNS tumors at our institute.
may seriously affect speech development and social and The results of the SOUND study will provide information on
neurocognitive skills, subsequently leading to a reduced quality the prevalence of hearing loss, tinnitus, and vertigo in a
of life [5-7]. prospective cohort of children with solid and CNS tumors. It
It is known that certain types of cancer treatment including will also give insight into the determinants of ototoxicity,
platinum agents, cranial irradiation, and brain surgery can induce especially the contribution of aminoglycosides, glycopeptides,
or enhance ototoxicity [3,8]. Platinum agents have been used and diuretics. Furthermore, the results will indicate whether it
successfully for treatment of solid and central nervous system is at all feasible to perform standardized audiological
(CNS) tumors [8]. Platinum accumulates in the inner ear and examinations in every childhood cancer patient with a potential
resides here for months to years after treatment [9]. It forms risk of ototoxicity. Eventually, this study may serve as a solid
crosslinks with DNA, leading to a transcription and replication basis for the selection of patients at risk that will benefit from
blockage and extensive production of reactive oxygen species innovative otoprotective interventions in the future.
(ROS). ROS cause inflammation and apoptosis, especially in
the outer hair cells, stria vascularis, and spiral ganglion cells Methods
[10,11]. Up to 70% of platinum-treated children develop
irreversible hearing loss and eventually 40% of them even need
Study Objectives
hearing aids at an early stage [12-14]. During cancer treatment The primary objective of the study is to investigate the
aminoglycosides, glycopeptides, and diuretics are often prevalence of hearing loss after cancer treatment in a prospective
prescribed as supportive care therapy [15-18], but knowledge cohort of pediatric CNS and solid tumor patients. Secondary
is lacking on their contribution to hearing loss development in objectives focus on examining the prevalence of tinnitus and
pediatric patients. Until now, the relation between supportive vertigo after cancer treatment, identifying clinical determinants
care treatment and ototoxicity has only been studied in small for ototoxicity, and investigating the feasibility of testing
pediatric cancer patient cohorts with a retrospective design. patients at risk for ototoxicity with standardized audiological
examinations.
Children diagnosed with CNS tumors or head and neck tumors
are often treated with high irradiation doses or surgery [19]. Study Design and Setting
Irradiation of normal ear structures cannot always be avoided, We will perform a national prospective cohort study in the
leading to middle and inner ear damage or vascular insufficiency Netherlands. This study is embedded in the Princess Máxima
of the ear [20-22]. Mechanical damage of ear structures caused Center, a national health care center that has been set up to treat
by surgical resection of tumors may also lead to hearing loss all children diagnosed with cancer. Collaboration with the
[23]. It may also be possible that the tumor itself causes hearing audiological department of Wilhelmina Children’s Hospital in
loss. Currently, standardized approaches for audiological the Netherlands has been established to perform audiological
monitoring during and shortly after therapy are lacking in testing of children of all ages. The selection, invitation, and
clinical practice. Beside this, adherence to scheduling of inclusion of patients takes place in the Princess Máxima Center.
audiological examinations is sometimes flawed, as the focus of The audiological assessment is age-adjusted, according to
clinicians is on cancer diagnostics and rapid start of treatment, recently published guidelines [24]. It will be performed before
rather than on monitoring side effects. Sometimes patients are the start of treatment, during cancer treatment according to
too ill to undergo audiological testing. Furthermore, treatment protocols, and within 3 months after the end of
age-appropriate audiological tests are often not applied, and treatment (Table 1). Information about the screening outcome
standardized tinnitus and vertigo screening is often not of the neonatal hearing screening is retrieved for all patients
implemented. Standardized audiological monitoring is important [25].
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Table 1. Stratification and time point for audiological examination based on treatment.
Audiological assessment
Treatment Stratum Before start treatment During treatmenta Within 3 months after
treatment
Platinum agents (cisplatin, carboplatin, oxaliplatin) 1 ✓b ✓ ✓
CNSc/ENTd irradiation 1e ✓ ✓
CNS/ENT surgery 1e ✓ ✓
No platinum agents, CNS/ENT irradiation, or CNS/ENT treatment 2 ✓ ✓
a
Time points for audiological assessments during treatment are based on recommendations in the childhood cancer treatment protocol.
b
The checkmark indicates that the assessment was performed at this time point.
c
CNS: central nervous system.
d
ENT: ear-nose-throat.
e
Patients are included in stratum 1 if audiological examinations are part of standard care; otherwise, they are included in stratum 2.
cerumen, infections, and perforations of the tympanic membrane
Study Population [28,29]. Tympanometry is routinely applied as an indicator of
Children aged 0 to 19 years who will be diagnosed with a CNS conductive hearing loss due to middle ear pathology. Static air
or solid tumor between January 2021 and January 2023 are pressure is varied systematically in the ear canal while an
eligible for participation in the study. They will be divided in acoustic stimulus of 226 or 1000 Hz is delivered. This procedure
two strata (Table 1). Stratum 1 consists of patients treated with measures the ability of the middle ear system to transfer
platinum agents (cisplatin, carboplatin, or oxaliplatin), low-frequency acoustic energy to the cochlea as a function of
CNS/ear-nose-throat (ENT) irradiation, or CNS/ENT surgery, static air canal pressure [30]. Abnormal functioning of the
and audiological examinations are part of standard care. Stratum middle ear due to a thickened tympanic membrane; presence
2 consists of patients not treated with therapies described in of middle ear fluid, for example, caused by acute otitis media;
stratum 1 or any patients in which audiological examinations or dysfunction of the Eustachian tube can be detected [31].
are not part of standard care. The independent contribution of
any comedication on ototoxicity development will be studied BERA will be performed for objectively measuring hearing
in stratum 2. thresholds to quantify the type and severity of hearing loss [32].
Electric activity of the VIII nerve and its central connections
Recruitment and Informed Consent are evoked by a broadband click stimulus or frequency-specific
Pediatric oncologists from the Princess Máxima Center will stimulus through a headphone, insert phone, or bone conductor.
select patients for invitation. For patients in whom audiological The responses can be measured by electrodes placed on the
examinations are not standard of care, written informed consent scalp and is represented as a registration of measured electrical
will be obtained from parents/guardians (patients) according to potentials as a function of time after stimulus presentation,
good clinical practice regulations. Withdrawal is possible at characterized by reproducible peaks at specific time delays
any time during the study without providing a reason. (latencies). No active cooperation is required, but a prerequisite
is that the patient is asleep or lies in a relaxed position to avoid
Study Procedures artifacts due to muscle activity.
All patients will be examined by standard audiological
Evoked otoacoustic emissions (OAEs) are sounds generated
examinations (Table 2), which always includes otoscopic
within the inner ear after presentation of a stimulus. OAEs are
inspection of the ears and tympanometry. Depending on the age
related to the nonlinear behavior of the cochlea, often referred
of the child, (a combination of) brainstem-evoked response
to as the cochlear amplifier. A clear relationship exists between
audiometry (BERA), distortion product otoacoustic emissions
the presence of normal OAEs and functional outer hair cells,
(DPOAEs), visual reinforcement audiometry (VRA),
which implies that OAEs can only be evoked in ears with normal
conditioned play audiometry, and extended high-frequency pure
hearing thresholds or very mild hearing loss (JMIR RESEARCH PROTOCOLS Diepstraten et al
Table 2. Audiological assessments per age category.a
Assessment Age categories
0-6 months 6 months-3 years 3-5 years 5-18 years
Check eligibility ✓b ✓ ✓ ✓
Determine stratum ✓ ✓ ✓ ✓
Check treatment plan ✓ ✓ ✓ ✓
Demographic data ✓ ✓ ✓ ✓
Audiological examination
Anamnesisc/case history ✓ ✓ ✓ ✓
Otoscopy ✓ ✓ ✓ ✓
Tympanometry ✓ ✓ ✓ ✓
Otoacoustic emissions ✓ ✓
Brainstem-evoked response audiometry ✓
Visual reinforcement audiometry ✓
Conditioned play audiometry ✓
(Extended high-frequency) pure tone audiometry ✓
Anamnestic tinnitus questions ✓d
Anamnestic vertigo questions ✓e
a
The listed audiological examination per age category provides an indication. Due to clinical circumstances or developmental status of the patients,
another more appropriate test might be chosen.
b
The checkmark indicates the assessment was given for these age groups.
c
During anamnesis children/parents are asked for hearing loss in the past, results of the neonatal hearing screening, ear-nose-throat surgery in the past,
and family members with (heredity) hearing loss.
d
Tinnitus screening will be performed for children 8 years and older.
e
Vertigo screening will be performed for children 10 years and older.
VRA and conditioned play audiometry are both subjective tests humming, whistling, sea noise, banging, blowing sound, like a
based on a conditioning procedure. For VRA, the child is machine, clicking, beep, like the wind, or like cars), the moment
conditioned to make a head turn and to look at a “reward,” for of onset (dates, after which chemotherapy course), laterality
example, a short movie or picture, every time a (left ear, right ear, or both), pitch (high vs low), perceived
frequency-specific stimulus is presented [35,36]. For conditioned loudness (graded according to a Likert scale 0-5) at the peak
play audiometry, children are conditioned to perform a moment, duration (intermittent, most, some of the time, or
motivation enhancing task when an auditory stimulus is continuous), annoyance degree (always annoyed, seldom
presented, for example, putting a block into a box [31,35]. annoyed, very annoyed, little annoyed), and severity with regard
Frequencies up to 8 kHz can be measured, but for ototoxicity to causing worry (not at all, slightly, sometimes, more severely)
monitoring, the range is preferably extended to the high [26]. Regarding vertigo, children 10 years and older will be
frequencies up to 12 kHz, as in an early stage, ototoxicity may asked whether they ever get dizzy. If the answer is yes, questions
affect the high frequencies [37]. follow on the moment of onset (dates, after which chemotherapy
course), presence of light-headedness (yes/no), tendency to fall
PTA is a subjective behavioral measurement of hearing
(yes/no), experiencing spinning or turning objects (yes/no),
thresholds. Conventional PTA measures the faintest tone a
sensation of turning or spinning (yes/no), loss of balance when
person can hear at selected frequencies. Hearing thresholds are
walking or running (yes/no), duration (intermittent, most/some
obtained via air conduction (0.25-8 kHz) by using headphones
of the time, or continuous), and severity (graded according to
and via bone conduction (0.5-4 kHz) by using a vibrating
a Likert scale 0-5) [27].
transducer. Additionally, extended high-frequency hearing
thresholds may be determined up to 12 to 14 kHz, depending Speech Audiometry
on the age of the child [31,34,38]. In case of hearing loss at the end of cancer treatment, speech
Anamnestic screening for tinnitus and vertigo will be performed audiometry is recommended to test the ability to hear and
during audiological assessments as a standardized procedure. understand speech. Several lists of words are offered to the child
Regarding tinnitus, children 8 years and older will be asked through headphones or a free field loudspeaker. The child is
whether they hear noise in their ears. If the answer is yes, asked to repeat the words. The number of correctly repeated
questions follow on the type of noise (ringing, buzzing, phonemes or words are recorded. The results are registered in
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a speech audiogram. The test reveals the amount of speech type and cumulative dose. Liver and kidney function will be
discrimination at various stimulus intensities and provides an measured during treatment. These results will be collected and
indication on the influence of hearing loss on communication. considered, as platinum agents, antibiotics, and diuretics are
Different test procedures are available, including determination (partially) excreted by liver and kidneys.
of the ear’s ability to discriminate speech in silence or in
Secondary outcomes also include the feasibility of standard care
different types of noise. Speech audiometry in children is often
audiological testing of all patients with solid and CNS tumors
used as a diagnostic test. In addition, the test can be useful to
treated with platinum, CNS/ENT irradiation, or CNS/ENT
evaluate the outcome of an intervention with hearing aids
surgery before and after childhood cancer therapy by using
[31,34,39].
standardized diagnostic tests, timing, and frequency of
Sample Size audiological evaluations in this population (stratum 1).
A power analysis based on two-sided CIs for one proportion Statistical Analysis
has been performed. The Clopper-Pearson exact formula for
Continuous variables will be reported with medians and ranges
computing binomial CIs was used. The method is based on the
while categorical variables with percentages. To assess
cumulative probabilities of the binomial distribution rather than
differences between patients with and without hearing loss,
an approximation [40,41]. A sample size of 367 patients
tinnitus, or vertigo, chi-square and Student t tests will be used
produces a two-sided 95% CI with a width (distance between
for categorical and continuous variables, respectively. In case
lower and the upper limit for the CI) equal to 1% when the
of violation of normality, Mann-Whitney U tests will be used.
sample size proportion is 35%. PASS software (NCSS, LLC)
has been used for computing the sample size. A logistic regression model will be estimated to investigate the
effect of risk factors such as platinum use and cumulative dose,
Outcomes type of CNS/ENT surgery, type of CNS/ENT irradiation and
Baseline Characteristics dose, type of comedication and its dose and levels, age at
diagnosis, and gender on ototoxicity at the end of treatment. To
Baseline variables will be collected including age; gender;
quantify the effect of prognostic factors on the risk of ototoxicity
weight; height; medical and audiological history; solid/CNS
at the end of treatment, odds ratios along with 95% CIs will be
tumor type; presence of neurofibromatosis (yes/no);
estimated. Statistical analysis will be performed with SPSS,
hydrocephalus (yes/no); which national or international cancer
version 26.0.0.1. (IBM Corp) [44].
treatment protocol will be applied; and whether a patient
receives treatment with CNS/ENT surgery, CNS/ENT In the presence of missing data, imputing techniques are used
irradiation, or platinum agents. [45].
Primary Outcome Measures Ethics Approval
The primary outcome is the prevalence of hearing loss at the The study protocol has been approved by the Clinical Research
end of cancer treatment in a prospective cohort of children with Committee of the Princess Máxima Center and by the Medical
CNS and solid tumors. Hearing loss is classified according to Research Ethics Committee Utrecht (Identifier 20-417/M), and
the Muenster classification [42]. The definition of sensorineural has been registered in the Netherlands Trial Register (NL8881).
hearing loss at the end of treatment will be >40 dB at 4 kHz
(corresponding to Muenster grade 2b) [42] measured by BERA, Results
VRA, conditioned play audiometry, or PTA. The SIOP Boston
criteria will be applied as a second grading for a reliable Inclusion started on January 4, 2021. Participant recruitment
determination of hearing loss [43]. and data collection are still ongoing. Patient inclusion will be
finished on January 1, 2023.
Secondary Outcome Measures
Secondary outcomes include the prevalence of tinnitus and Discussion
vertigo, and the treatment components that may be associated
to hearing loss, tinnitus, and/or vertigo development. Tinnitus Study Rationale
and vertigo will be measured by the aforementioned study Ototoxicity is a serious adverse event of childhood cancer
procedures. The definition of tinnitus at the end of treatment treatment. However, the prevalence of hearing loss, tinnitus,
will be “a sensation of a noise in the ear or head when no and vertigo during and shortly after treatment has never been
apparent source for the noise is evident” [26]. The definition of studied in large prospective pediatric oncology patient cohorts.
vertigo is “an abnormal sensation of motion,” which can occur To date, the association of clinical characteristics and treatment
in the absence of motion or when a motion is sensed inaccurately components on the development of ototoxicity is not fully
[27]. Treatment components of included patients that will be understood. Therefore, we will investigate the feasibility of
collected include total cumulative dose of cisplatin, carboplatin, testing all patients with a potential risk on ototoxicity with
and oxaliplatin; irradiation type (photon or proton) and total standardized audiological examinations. The prevalence and
dose in Gray (especially on inner ear structures); type of determinants of hearing loss, tinnitus, and vertigo will be
CNS/ENT surgery, cerebral shunt, or Ommaya reservoir; investigated in a prospective cohort of childhood cancer patients.
aminoglycoside type, levels, and total cumulative dose; Accurate audiological testing and timely detection of ototoxicity
glycopeptide type, levels, and total cumulative dose; and diuretic will identify novel compounds at risk for ototoxicity and create
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awareness, which may lead to improved patient care and Limitations
improved quality of life. Furthermore, we aim to collect First, it is important to realize that pediatric oncology patients
high-quality data on the relation between disease status, type can be critically ill at the time of presentation at the hospital.
of treatment, and audiological functioning in children with solid In that case, it may not be feasible to perform baseline
and CNS tumors before and shortly after treatment. In the future, audiological examination. For these selected children, we
these data could be used to identify children who are at risk and decided to use audiological anamnesis to exclude any type of
might benefit from otoprotective agents that are currently under pre-existent hearing loss. Second, it is possible that patients will
development. receive medication (eg, antibiotics and diuretics) in shared care
centers, which are not reported and may lead to underreporting
comedication.
Acknowledgments
The study is funded by internal funding, Paediatric Oncology Foundation Rotterdam and the core funding of the Princess Máxima
Center. There is no contribution of commercial organizations.
Data Availability
Data sharing is not applicable, as no data set is currently available for analysis in this study protocol. A data transfer agreement
between the Wilhelmina Children’s Hospital/University Medical Center Utrecht and the Princess Máxima Center is available to
transfer audiological data.
Authors' Contributions
MvdHE, MvG, FAD, and AJMM contributed by receiving ethical approval for the Study on Prevalence and Determinants of
Ototoxicity During Treatment of Childhood Cancer (SOUND). FAD and AJMM were major contributors in writing the manuscript.
MvdHE, MvG, SLAP, AEH, GOJ, RJS, AJMM, and FAD all contributed to the study design and critically revised the manuscript.
AEH revised the audiological part of the Methods section. MF wrote the statistical analysis section of the manuscript. All authors
read and approved the final version of the manuscript.
Conflicts of Interest
None declared.
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Abbreviations
BERA: brainstem-evoked response audiometry
CNS: central nervous system
DPOAE: distortion product otoacoustic emission
ENT: ear-nose-throat
OAE: otoacoustic emission
PTA: pure tone audiometry
ROS: reactive oxygen species
SOUND: Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer
TEOAE: transiently evoked otoacoustic emission
VRA: visual reinforcement audiometry
Edited by T Leung; submitted 15.10.21; peer-reviewed by P Brock, L Hunter, E Mohammadi, Y Alabdallat; comments to author
04.02.22; revised version received 10.02.22; accepted 11.02.22; published 07.04.22
Please cite as:
Diepstraten FA, Meijer AJM, van Grotel M, Plasschaert SLA, Hoetink AE, Fiocco M, Janssens GO, Stokroos RJ, van den Heuvel-Eibrink
MM
A Study on Prevalence and Determinants of Ototoxicity During Treatment of Childhood Cancer (SOUND): Protocol for a Prospective
Study
JMIR Res Protoc 2022;11(4):e34297
URL: https://www.researchprotocols.org/2022/4/e34297
doi: 10.2196/34297
PMID:
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©Franciscus A Diepstraten, Annelot JM Meijer, Martine van Grotel, Sabine LA Plasschaert, Alexander E Hoetink, Marta Fiocco,
Geert O Janssens, Robert J Stokroos, Marry M van den Heuvel-Eibrink. Originally published in JMIR Research Protocols
(https://www.researchprotocols.org), 07.04.2022. This is an open-access article distributed under the terms of the Creative
Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The
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